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6 184

S Seppä and others Primary 184:6 R225–R242 Review

MANAGEMENT OF Diagnosis and management of primary amenorrhea and female delayed

Satu Seppä1,2 , Tanja Kuiri-Hänninen 1, Elina Holopainen3 and Raimo Voutilainen 1 Correspondence 1Departments of Pediatrics, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland, should be addressed 2Department of Pediatrics, Kymenlaakso Central Hospital, Kotka, Finland, and 3Department of Obstetrics and to R Voutilainen Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland Email [email protected]

Abstract

Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary , psychosocial maturation and reproductive capacity. In , is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥ 15-year-old females with developed secondary sexual characteristics and normal growth or in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche 3 years after (start of development) or 5 years after thelarche, if that occurred before the age of 10 years. A variety of disorders in the – pituitary–ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic , gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero–vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary

European Journal of depending on both the etiology and the patient; with timely etiological diagnostics may be attained even in those situations where no curable treatment exists.

European Journal of Endocrinology (2021) 184, R225–R242

Invited Author’s profile Raimo Voutilainen is a pediatric endocrinologist and emeritus professor in pediatrics at the University of Eastern Finland and Kuopio University Hospital in Kuopio, Finland. His research fields have included both translational and clinical studies on adrenal and gonadal function during fetal, childhood and adult life. Adrenal tumors, congenital adrenal hyperplasia, premature , pubertal development, and later health consequences of small and large birth size, and maternal pre-eclampsia have been his clinical research areas. Hair steroids and their relationship to risk is one of his current research interests.

https://eje.bioscientifica.com © 2021 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-20-1487 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 04:20:59PM via free access

-20-1487 European Journal of Endocrinology https://eje.bioscientifica.com gradual breasttissueanduterinegrowth,pubertalgrowth . Increasingestrogenlevelsingirlsresult converted toestrogensingranulosacellsbyFSH-induced follicular theca cells to produce , which are a progressivefashion( (LH)andfollicle-stimulating(FSH)in stimulate thesecretionofgonadotropinsluteinizing gland,wherethey system toreachtheanteriorpituitary are secretedintothehypothalamic–pituitary–portal hormone (GnRH)secretion.EpisodicGnRHboluses gradual increaseinhypothalamicgonadotropin-releasing and -relatedfactorsplayarole( determined by , also environmental, nutritional HPG axisarenotfullyknown.Althoughtheystrongly precise mechanismsunderlyingthereactivationof HPG axisisinactiveuntilthebeginningofpuberty. The axis described as minipuberty ( (HPG) activation ofthehypothalamic–pituitary–gonadal months, thehumaninfantexperiencesatransient beginning alreadyinfetallife( systems thatinteractinanordered,progressivepattern biological controliscomplexinvolvingmultipleendocrine psychosocial maturation and reproductive capacity. Its sexualcharacteristics, and theacquisitionofsecondary height andbodycomposition,accrualofbonestrength adulthood characterized by theattainmentofadult Puberty is theperiod of transitionfrom childhood to Normal pubertyandpubertalmarkers hormone. GnRH, -stimulating hormone;LH,luteinizing sexual characteristics.FSH,follicle-stimulating hormone; Hypothalamus–pituitary–ovarian (HPO)axisandsecondary Figure 1 Review Reactivation oftheHPGaxisischaracterizedbya , Hypothalamus LH, FSH Pituitary GnRH phase Luteal + phase Follicular - 1 ) ( - +

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Duringthefirst of bonestrength.Theendometriumproliferatesand spurt, feminine distribution and accrual decline hasbeenreported( 13 well-nourished populations indevelopedcountries( median ageatmenarche hasremainedmorestableacross andlifestyle(reviewed in ( in manycountries,duetoimprovedgeneralhealth, significantly between the 19th and the mid-20th centuries 2013 ( decreased byalmost3monthsperdecadefrom1977 to analysis, the age at pubertal onset based on thelarche had has beenreported( downward seculartrendintheonsetofbreastdevelopment puberty between8.5and13yearsofage( In mostpopulations,95%ofgirlsexperiencetheonset of 80% ofthisvariationisgeneticallydetermined( years aftermenarche (reviewed in( ( 9 thelarche atTanner stageIVofbreastdevelopment( in girls( in ( clinical signsandadrenalandrogensecretion(reviewed or followgonadarche witha widevariationintiming, adult typebodyodor. Adrenarche mayprecede,overlap hair,the development of pubic and axillary and sexualcharacteristicssuchas associated withsecondary of adrenalandrogenprecursorsinmid-childhood.Itis the adrenalcortexresultinginincreasedproduction and functionaldevelopmentofthezonareticularisin Primary amenorrhea 5 , ). ItisrarebeforeTanner stageIIIofbreastdevelopment ). Pubertaldevelopmentiscompletedapproximately1.5 , 6 7 14 Pubertal timingvariesinthepopulation,and50to ). Developmentofpubichair, , isusually )). Menarche isregarded asalatemarkerofpuberty , 12 15 6 ). Theaverageageofmenarche hasdecreased ). Typically, itoccurswithin2to3yearsafter ), althoughasmallbutstatistically significant 8 , 11 , Downloaded fromBioscientifica.com at09/25/202104:20:59PM 12 11 ). Accordingtoarecentmeta- , 16 ). Alargestudyfromthe 10 1 184 , )). 10 4 :6 )). Afterthat,the ). 1 ). However, a 1 , R226 3 , 5 10 , 11 via freeaccess 8 1 ). , , , European Journal of Endocrinology weight development,nutritional status,medications, with heightandweightcharts, trendsinheightand should include a thorough personal medical history amenorrhea Evaluation oftheadolescent withprimary primary amenorrhea Evaluation oftheadolescentwith careclinicianshasbeenpublished recently( primary gynecologists. Acomprehensivereviewtargeted at is primarilytargetedatpediatricendocrinologistsand amenorrhea are presented in American descentexists.Potentialetiologiesofprimary our knowledge,norecentreportsontheEuropean or hypogonadotropic hypogonadism( to begonadaldysgenesis,Müllerianagenesis,and amenorrheahavebeenreported etiologies ofprimary development withnomenarche. Themostcommon can leadtodelayedorstalledpuberty, ornormalpubertal amenorrhea anomalies. Underlying causes of primary other endocrineglands,andcongenitalutero–vaginal causing hypergonadotropichypogonadism,disordersof hypogonadotropic hypogonadism,gonadaldisorders disorderscausing as hypothalamicorpituitary amenorrheacanbecategorized Etiologies ofprimary relative proportions differ from each other( amenorrheaaresimilar,and secondary their inadolescents( for longerthan45-dayintervals months. Oligomenorrheaistheabsenceofmenstruation for 3monthsorthecessationofirregularmenses6 amenorrhea isdefinedasthecessationofregularmenses has startedbeforetheage10years( thelarche ( amenorrheashouldbeinitiated3yearspost- of primary )( females withoutsignsofpubertaldevelopment(i.e. characteristics andnormalgrowthorin in amenorrhea is defined astheabsence of menarchePrimary Definition ofprimaryamenorrhea in 1991and13.13years2006( Danish study, estimatedageatmenarche was13.42years Hispanic white and Mexican–American girls. In a large earlier innon-Hispanicblackgirlscomparedwithnon- 12.43 years ( Review ≥ Although the majority of the causes of primary Although themajorityofcausesprimary 15-year-old females with developed secondary sexual 15-year-old females with developed secondary 13 14 ), orwithin5years,ifbreastdevelopment ). In that study, menarche was significantly Fig. 1 ) ( 13 , 17 Table 1 ). Furthermore,evaluation S Seppäandothers 11 ). 17 . This review article , 19 17 ). However, to ). Secondary ). Secondary ≥ 13-year-old 18 ). 18 17 ). ). measurement ofFSH,LH,,thyroid-stimulating amenorrhea. findings relatedtoprimary internal reproductiveorgans. with abdominalultrasonographyissufficienttoevaluate In mostcases,theexternalgynecologicalexamination circulating estrogensareoratleasthavebeenpresent. sexualcharacteristicsindicatethat presence ofsecondary differential diagnoses.Normalbreastdevelopmentand examination is needed to considerthe broad spectrum of development should be reviewed. A full physical diseases shouldbeincluded.Timing ofpossiblebreastand , ,midlineabnormalitiesandchronic of menarche of ofthecloserelatives,andanyhistory age atpubertalonsetofbothparentsandsiblings, family history, includingchildhoodgrowthpatterns, If pubertaldevelopmentisdelayedorstalled,acomplete psychosocial functioningandtheintensityofexercise. orsymptomsofchronic diseases, fractures, history growth and puberty (CDGP) is the most common cause of pubertal HPG axis activation. Constitutional delay of Delayed pubertyischaracterized bytheabsenceof of growthandpuberty(CDGP) Self-limited delayedpuberty/constitutionaldelay low-normal range. low orwithinthe LH maybeundetectable,very levels.Serum FSHand at hypothalamicorpituitary Hypogonadotropic hypogonadismiscausedbydisorders hypogonadotropic hypogonadism Etiologies causing in hypoestrogenicstates. bone mineraldensity(BMD)testingshouldbeconsidered isasignificantriskfactorforboneloss, for hypergonadotropicetiologiesispresented.Because serum FSH and LH concentrations. In amenorrheaandlowornormal patient withprimary Figure 2 and17-hydroxyprogesterone(17-OHP). serum (free),DHEAoritssulfate(DHEA-S), Signs of indicate measurement of ( information toruleoutorganiccausesofamenorrhea boweldiseasewillgenerally providesufficient inflammatory complete bloodcountandscreeningforceliac hormone (TSH),freethyroxine(FT4),(E2), Primary amenorrhea 20 ). Pregnancytestshouldbetakenwithlowthreshold. In theabsenceofsignsandrogenexcess, representsanalgorithmfortheapproachto Downloaded fromBioscientifica.com at09/25/202104:20:59PM Table 2 https://eje.bioscientifica.com 184 presentsfeaturesor Fig. 3 :6 ,

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European Journal of Endocrinology https://eje.bioscientifica.com self-limited delayedpuberty areknown( acceleration isemphasized( delay in the development of pubertal signs and growth girls) ( of pubertaldevelopmentbytheboneage13years in are achieved at a normal (i.e. the onset of signs to chronological age, but the developmentalmilestones than theirpeers( early childhood,andconsequentlytheymaybeshorter subjects withCDGPhavehaddelayedmaturationduring an extremevariantofnormalpubertaltiming( with pubertaldelay( delayed pubertyingirlscomprisingupto30–56%of FSH, folliclestimulatinghormone;GnRH,gonadotropin-releasingLH,luteinizinghormone. Adrenals Pituitary Normogonadotropic hypogonadism Premature ovarianinsufficiency Hypergonadotropic hypogonadism Medications/drugs Thyroid Pituitary glandorstalkdamage Combined pituitaryhormone Syndromic congenital Congenital hypogonadotropic Functional hypothalamic Constitutional delayofgrowthand Hypogonadotropic hypogonadism Condition Table 1 Review deficiency puberty puberty/self-limited delayed Althoughonlyasmallnumber ofgeneticcauses deficiencies) (often multiplepituitaryhormone hypogonadotropic hypogonadism hypogonadism amenorrhea 1 ). Ifadrenarche isalsolateinagirlwithCDGP, the Potential etiologiesofprimaryamenorrhea. 1 ). Boneageisusuallydelayedcompared 1 , 21 , 7 22 ). ). Itcanbeconsideredas S Seppäandothers Imperforate Agenesis, transverseseptum,distalatresia Müllerian agenesis;cervicalagenesis,androgeninsensitivitysyndrome, Polycystic ovarysyndrome;tumors(-orestrogen-secreting) Non-classic congenitaladrenalhyperplasia,insufficiency,tumor(androgen- Hyperprolactinemia ,gonadaldysgenesis46,XX-e.g.,mutationsinsteroidogenicgenes Anesthetics, anticonvulsants,antipsychotics,gastrointestinalmotilityagents orhyperthyroidism Adenomas andothertumors(i.e.,,Cushing’sdisease,, CHARGE syndrome,WaardenburgHartsfieldcongenitaladrenal GnRH deficiencyandanosmia(Kallmannsyndrome);isolatedcongenital ,othereatingdisorder,excessiveexercise,stress,psychiatricillness, secreting) autoimmune syndrome,irradiationorsurgery,, LH receptorgene,othergeneticetiologies;autoimmuneoophoritis,polyglandular dysgenesis 46,XY-e.g.,mutationsinsteroidogenicgenes, (17 hydroxylasedeficiency,aromatasedeficiency),FSHreceptorgene,gonadal (highdose),exogenousandrogens(transgendercare inhibitors; Oralcontraceptives,alcoholabuse,heroin,cocaine,marijuana, (metoclopramide, domperidone,ranitidine?),opiates;selectiveserotoninuptake therapy surgery, trauma,pituitaryapoplexy,vascularlesions,emptysellasyndrome,radiation hemochromatosis, sarcoidosis, Langerhans cell histiocytosis, granulomatous diseases); suprasellar cysts,mucocele),Infiltrativedisorders(autoimmunehypophysitis, ); cysts(Rathke’scleftcyst,arachnoid,dermoid,epidermoid, syndrome syndrome, Laurence–MoonGordonHolmesBardet–Biedl hypodontia), septo-opticdysplasia,holoprosencephaly,encephalocele,Prader–Willi hypoplasia, 4Hsyndrome(hypomyelination,hypogonadotropichypogonadism, hypogonadotropic hypogonadism chronic disease(e.g.celiacdisease,inflammatoryboweldisease) 1 ), ageneticbasis 23 ). Many to havenegativeoutcomes from theircondition( milder formsofdelayedpuberty whoarenotpredicted this review. evaluation aredescribedinthefollowingchapters of causes ( can bediagnosedonlyafterexclusionofotherunderlying prepubertal FSHandLHconcentrations.However, CDGP ofdelayedpubertalonset( family history is evident,since50to75%ofgirlswithCDGPhave a development isdescribed later inthisreview. Before is preferredtoethinyl estradiol ( elects to betreated, transdermal or oral17 Primary amenorrhea Expectant observation isappropriate in girlswith Expectant observation Evaluation revealsdelayedpubertaldevelopmentwith 23 ). DifferentialdiagnosesofCDGPandtheir Causes Downloaded fromBioscientifica.com at09/25/202104:20:59PM SOX9, SRY,WT1,NR5A1 23 ). Induction of pubertal 184 :6 21 , 24 β ). -estradiol , 1 R228

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European Journal of Endocrinology causes ( chronic anovulationthatisnot duetoidentifiableorganic Functional hypothalamicamenorrhea (FHA)isaformof duration ofinsultwillresult inalongertimetoreversal. inability toobtainpeakbone massandinfertility. Alonger Furthermore, hypoestrogenismmayleadtoboneloss, turn leadstopoorendometrialgrowthandamenorrhea. causing hypoestrogenism(reviewedin( ovarian functionthus full folliculogenesisandovulatory and LHFSHlevelsthatareinsufficienttomaintain GnRH drivemanifestsasreducedLHpulsefrequency development (reviewed in ( hypogonadism anddelayedorarrestedpubertal is HPGaxissuppressioncausinghypogonadotropic development ( females withdelayedpubertyorincompletepubertal Functional etiologyisfoundinapproximately20%of Functional hypogonadotropichypogonadism paragraphs). (FHA) shouldbecarefullyexcluded(presentedinthenext reasons causingfunctionalhypothalamicamenorrhea considering hormonaltreatmentofCDGP, life-style CHH,congenitalhypogonadotropichypogonadism. Eating disorder Complete androgeninsensitivitysyndrome Signs ofhypercortisolism Signs ofhyperandrogenism Turner syndromestigmata CHH-associated phenotypes Abdominal palpation Thyroid examination Pubertal development Growth charts Clinical evaluation Specific symptoms Sexual activity Head trauma/surgery (brain,) Chemotherapy Medications Psychosocial distress Exercise Eating habits,diet Changes inweight Family historyof History Parameters evaluated Table 2 Review 20 Summary ofhistoryandclinicalevaluationinthework-upprimaryamenorrhea. ). 1 , 22 ). Theunderlyingpathophysiology 1 )). Functional reduction in S Seppäandothers Low BMI,lanugo,dryskin,coldextremities,bradycardia Scanty axillaryandpubichairinassociationwith(full)breastdevelopment Striae, moonface,buffalohump,hypertension,centralobesity Acne, malepatternbaldness,,clitoralenlargement,voicedeepening Short stature,webbedneck,lowhairline,skeletalandcardiovasculardefects Midline abnormalities,mirrormovements,dentalagenesis,skeletalor Tumor, Tanner staging Weight loss,stuntedgrowth Headache, nausea,changesinvision,abnormalthirst,galactorrhea, Growth chart Delayed puberty,infertility,earlymenopause Parameters checked 20 cardiovascular defects,hearingloss, constipation/diarrhea anosmia, vasomotorsymptoms(hotflashes,nightsweats),abdominalpain, )), whichin functional hypogonadotropic hypogonadism,andthere genetic mutationsmaypredispose tothedevelopmentof running) areriskfactorsfor amenorrhea( advantage (i.e.gymnastics, figure skating,cheerleading, individuals. Sportsinwhich leannessmayconferan less fatandmoremusclecomparedwithnonathletic hypogonadism may develop even at normal weight with (reviewed in( Glucocorticoids alsoinhibittheeffectsofE2inuterus hormone (CRH)andcortisolsuppressGnRHsecretion. described (reviewedin( reduction inGnRHdrivewomenwithFHAhasbeen (HPA)of thehypothalamic–pituitary–adrenal axisand on theHPGaxis( cytokinesmayhaveanimpact levels ofproinflammatory (reviewed in( adaptive responsetochronicmetabolicenergydeficiency Hypogonadotropic hypogonadismandFHAdevelopasan and cysticfibrosis)maycauseHPGaxissuppression. celiac disease,chronicrenalsicklecellanemia bowel disease, inflammatory disease (e.g. anorexia nervosa, excessive exercise orrestrictive eatinghabits,alsochronic Primary amenorrhea In athleticindividuals,hypogonadotropic In additiontolife-stylecauses,forexample,stress, 20 25 )), butalsohypercortisolism, andelevated )). 1 ). Anassociationbetweenactivation 20 Downloaded fromBioscientifica.com at09/25/202104:20:59PM )). Bothcorticotropin-releasing https://eje.bioscientifica.com 184 :6

26 ). Certain R229 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com 17-hydroxyprogesterone. congenital adrenalhyperplasia; PCOS,polycysticovarysyndrome;TSH,thyroid-stimulating hormone; 17-OHP, stimulating hormone;FT4,free thyroxine; hypogonadism. CBC,complete bloodcount;CHH,congenitalhypogonadotropichypogonadism; E2,estradiol;FSH,follicle- Algorithm fortheapproachto the patientwithprimaryamenorrheaandhypogonadotropic ornormogonadotropic Figure 2 Review DEVELOPMENT PUBER OR NORMAL ARRESTED PUBER DELA PUBER ARRESTED DELA DELA NORMAL NO MENARCHE DEVELOPMENT, examinatio physical History and YED OR YED OR YED PUBER TA TY PUBER L n

TA TY TY L

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R230 via freeaccess European Journal of Endocrinology may persistforyears.Treatment shouldrestoreHPO most endocrineandmetabolic functions,amenorrhea normal, E2lowandLH/FSH ratioelevated( syndrome (PCOS), LH and FSH may be polycystic ovary InpatientswithFHAand underlying pattern ispreserved. than thatseeninCushing’s syndrome,andthecircadian any chronicillness.Theincreaseincortisolsecretionisless are inthelowerrangeofnormal,similartothatseen in and validityshouldbefollowed( Endocrine SocietyguidelinestoassureE2assayreliability be consideredafteranendocrinologistconsultation.The for amenorrheaexists,aGnRHstimulationtestshould hypogonadism ( differentiate FHA fromothertypesofhypogonadotropic the responsetoGnRHisonlyfeaturethatmay with E2 consistently lower than 20 pg/mL (73 pmol/L), deficient gonadotropinsecretion.However, infemales hormonesissufficienttoestablish of basalpituitary FSH comparedwithbaselinelevels).Usually, evaluation (definedasatwo-orthree-foldriseinLHand preserved but acutegonadotropinresponsetoGnRHstimulationis ( serum LHandnormalFSH(usuallyhigherthanLH)levels parameters typically reveal low or low-normal Laboratory are essential.Chronicdiseaseshavetoberuledout. and acarefulevaluationforpsychosocialinfluences (typically weightlossandsometimesstuntedgrowth) hypogonadism (CHH)( bases offunctionalandcongenitalhypogonadotropic is evidenceforheterozygousoverlapbetweenthegenetic stimulating hormone;LH,luteinizingPOI,prematureovarianinsufficiency. Algorithm fortheapproachtopatientwithprimaryamenorrheaandhypergonadotropichypogonadism.FSH,follicle- Figure 3 Fig. 2 Review High FSHandLH In a suspicion of FHA, review of the growth curves In asuspicionofFHA,reviewthegrowthcurves Although recovery of normal weight will normalize ofnormalweightwillnormalize Although recovery ). Serum E2 is typically 20 ). Ifnoevidentreason(e.g.weightloss) pelvic surger chemotherapy or History ofirradiation, 27 ). < 50 pg/mL (184 pmol/L), 28 y S Seppäandothers ). InFHA,TSHandFT4

20 ). No Ye s karyotype Review axis function through behavioral changes and energy axis functionthroughbehavioralchangesandenergy associated withanabsent senseofsmellistermed of adolescentgirlswithpubertal delay( puberty ( network. Itischaracterized byabsentorincomplete migration orinthematuration oftheGnRHneuronal due todevelopmentaldefectsintheGnRHneuron CHH isararegeneticdisordercausedbyGnRHdeficiency hypogonadism (CHH) Congenital hypogonadotropic toimproveBMDinadolescentswithFHA( recommends againstbisphosphonates,testosterone,and may precedemenstruation.TheEndocrineSociety for patientsatriskpregnancybecauseovulation However, oralcontraceptivesshouldbeconsidered the underlyingpathologyandbonelossmaycontinue. gaining menses or improving BMD, as they may mask suggests againstoralcontraceptivesforthepurposeof 17 therapy (12months),short-termuseoftransdermal density testing after12 months of undernourishment ( therapy (HRT)( of amenorrheabeforeconsideringhormonereplacement BMD measurementisrecommendedafter6to12months for psychologicalsupportmustbeevaluated( abnormalities mayrequireinpatienttreatment.Theneed with bradycardia,hypotension,orthostasis,orelectrolyte exercise activity, stressreduction,andweightgain.Patients imbalance correction by improved nutrition, decreased Primary amenorrhea β Iatrogenic POI -estradiol maybetried.TheEndocrineSociety After a reasonable trial of non-pharmacological 10 , 30 46,XY 45,X0 46,XX 20 ) affectingapproximately 10 to20% ). NICE guideline recommends bone ). NICEguidelinerecommendsbone Downloaded fromBioscientifica.com at09/25/202104:20:59PM 46,XX Gonadaldysgenesis Tu 46,XY 46,XX othergeneticcauses https://eje.bioscientifica.com rner syndrome(alsomosaics) Gonadaldysgenesis 184 :6 21 20 , 22 ). In FHA, ). InFHA, 20 ). CHH R231 ). 29 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com / prokineticin 2 receptor ( fibroblast growthfactor1( mutationsinautosomalgenes,for example, carrying to avariabledegreeofpubertaldevelopmentinfemales exist ( case reportsconcerningfemaleswithreversibleCHH amenorrhea ( with secondary resembles FHA( be underdiagnoseddueto clinicalpresentationthat absent toalmostnormal ( up to50%ofwomen( in studies, absentbreastdevelopment wasobserved reported innearly90%ofwomenwithCHH.Inmost and onenobreastdevelopment( amenorrhea,eighthadpartial, threecomplete, primary ( reproductive phenotypesfromCDGPtocompleteCHH function mutationsin ( patients ( reversible hypogonadotropichypogonadisminsome hypogonadism withanarrestofpubertaldevelopment, complete hypogonadotropichypogonadismtopartial genes) ( oligogenicity (i.e.interactionofmutationsintwoormore is incompleteandexpressivityvariableprobablydueto clinical pictureissimilartothatinCDGP. Itspenetrance to diagnose, particularly in early when the of casesremainsunclear( pathophysiological basisofCHHinapproximately50% to acteitheraloneorincombination.However, the date, mutationsinover30geneshavebeenidentified CHH, accounting for 16 to 40% of patients ( are themostfrequentcausesofautosomalrecessive Loss-of-function mutationswithintheGnRHreceptor impaired regulation of GnRH secretion (reviewed in ( andGnRHneuronaldevelopmentbut normal olfactory are found ( defects, andcardiovasculardefects( brain defects,cleftlip/palate,dentalagenesis,skeletal movement disorders, sensorineural hearing loss, midline movements (synkinesis),unilateralrenalagenesis,eye reproductive phenotypesassociatedwithCHHaremirror ( embryogenesis placode andmigratetogetherintotheCNSduring neuronsoriginatefromtheolfactory GnRH andolfactory abnormal fetaldevelopmentofGnRHneurons;both .syndromeisaresultfrom 33 GNRHR Review , CHH maymanifestaspartialhypogonadism,leading CHH istermed‘isolated’whennoanatomicaldefects 38 32 ). Inaseriesoftwelvepatients,ten(83%)had 1 ) ( ). , 32 1 10 34 , ). Thespectrumofphenotypesiswidefrom ). Isolated CHH is typically associated with , 10 33 35 31 ) or normal pubertal development , , ). With lowerprevalence,othernon- 39 36 ). ). GNRHR , 37 37 PROKR2 FGF1 , 1 ). Biallelic,partialloss-of- ). CHHcanbechallenging 39 39 causeawidespectrumof , ). Pubarche rangedfrom 33 ), prokineticin2( S Seppäandothers 40 ). However, only few ), and GnRH receptor 1 ). PartialCHHmay 38 , 10 ). Amenorrheais ). 1 , PROK2 31 ). To 6 )). )

pituitary gonadotropecells.Mutationsin pituitary ,,ventromedialhypothalamus,and gene ( alternatively known asDAX-1orphan nuclear receptor Nuclear receptorsubfamily0groupBmember1( syndrome undergoprecociouspuberty(reviewedin( genitalia. TheminorityofindividualswithPrader–Willi hypogonadotropic hypogonadism and underdeveloped development expressedaslackofpubertalgrowthspurt, or delayedpuberty. Mostundergoincompletepubertal caused byimprintingdisorders,isassociatedwithabsent hypodontia) syndrome.Prader–Willi syndrome,frequently (hypomyelination, hypogonadotropic hypogonadism and bulb aplasia)syndrome,Waardenburg syndrome,and4H development, genitalanomalies,earolfactory atresia ofthechoanae,retardationgrowthand are forexampleCHARGE(coloboma,heartmalformations, syndromic formsofCHH.SyndromesassociatedwithCHH obesity ordysmorphicfeaturescanleadtothediagnosisof such asdelayedcognitivedevelopmentassociatedwith hypogonadotropic hypogonadism.Specificphenotypes, Several complexsyndromesareassociatedwith CHH-associated phenotypes by performing an exploration of the complete pituitary by performinganexploration ofthecompletepituitary hormone defects have to be ruled out other pituitary to evaluatebonehealth( and unilateralrenalagenesis, andaBMDmeasurement lesions, ultrasonographyto visualizetheovaries,uterus work-up includescranialMRItoruleouttumorsorother diagnosis, prognosisandgeneticcounsellinginCHH.Its normal range( E2 (usingsensitiveassays)maybewithinthelow- partial pubertaldevelopment,serumgonadotropinsand FSH andLHmaybeundetectablelow, or in thosewith the differentialdiagnosisofCDGPandCHH( 22 in adolescencewithabsenceofpubertalgrowthspurt( growth duringchildhoodandbecomeshortfortheirage growth rate, usually subjects with CHH have steady linear Although CHH cannot be distinguished from CDGP by Similar toCDGPandFHA,CHHisanexclusiondiagnosis. Evaluation forCHH and hypogonadotropichypogonadism( obesity, alterationsinimmunefunction,delayedpuberty the leptin-receptorgene( with hypogonadotropichypogonadism( congenital X-linkedadrenalhypoplasiathatisassociated Primary amenorrhea ). Moreover, basalgonadotropinlevelsarenotusefulin DAX1 ) isimportantforthedevelopmentof 10 , 43 ). Genetictestingisrecommendedfor Downloaded fromBioscientifica.com at09/25/202104:20:59PM LEPR 30 ). IntheevaluationofCHH, ) causehyperphagia,severe 184 42 :6 41 ). ). Mutationsin NR0B1 1 ). Serum NR0B1 R232 cause 1 via freeaccess )). 1 ), ,

European Journal of Endocrinology syndrome orCushing’s disease).OtherCNS tumors and Cushing’sthe adrenalcortex(termedpituitary-dependent adenomas thatstimulateexcessive cortisolsecretionfrom Corticotropinomas are ACTH-producing pituitary and non-functioning adenomas (reviewed in ( (5–15%), gonadotropinomas,thyrotropinomas followed bycorticotropinomas(30%),somatotropinomas adenomas inadolescenceareprolactinomas(46–66%), functional. AccordingtoGuaraldi functional adenomasaremorecommonthannon- tumors.Inadolescents, representing 2–8.5% ofpituitary adenomasarerareinchildren andadolescents Pituitary Tumors andcysts asymptomatic hyperprolactinemia( hyperprolactinemia, hastoberuledoutinsubjectswith Macroprolactinemia, which is a cause ofphysiological mechanismofprolactinsecretion. in theinhibitory prolactin levelsareusuallytheresultofdysregulation once incasesofmildhyperprolactinemia.Mildlyelevated to stressorotherfactors,itshouldbemeasuredmorethan termed ( hormone deficiencies accompanied by multiple pituitary gonadotropic hypogonadism ( disturbed gonadotropinsecretionwithnormo-orhypo- GnRH pulserhythmandsecretion,resultingin prolactin concentrationsinhibitnormalhypothalamic effect ofdopamineonprolactinsecretion( hyperprolactinemia viatheinterferenceofinhibitory with GnRHorgonadotropinsynthesissecretion,by stalkcompressioninterfering hypothalamus orpituitary 2 traumatic causes(reviewedin( diseases, irradiation,surgery, apoplexy, pituitary and secreting or non-secreting tumors, infiltrative orsystemic onset ofexposure.Theycanbeclassifiedintohormone- may leadtodelayedorstalledpubertydependingonthe Organic causesofhypogonadotropichypogonadism hypogonadotropic hypogonadism Acquired causesof of pubertaldevelopmentaredescribedlaterinthisreview. normal senseofsmell( CHH wereanosmicorhyposmicdespiteself-reported test,since50%ofthosewith standardized olfactory axis ( ). Pathophysiologyisusuallymediatedeitherby Review As serumprolactinconcentrationmayriseinresponse 30 ). Senseofsmellshouldbetestedwitha 44 45 ). Inductionandmaintenance ). 4 ). These conditions may be S Seppäandothers et al. 45 25 , , , themostcommon 46 48 ) ( ). 1 , Table 1 25 , 47 ). High ,

49 Fig. )). other pituitary adenomas and macroadenomas causing other pituitary treatmentformicroprolactinomas.In are theprimary and 100ng/mL(~500–2000mU/L)(reviewedin( 4000–20 000mU/L),andinotheradenomasbetween25 macroprolactinomas between200and1000ng/mL(~ between 100and250ng/mL(~2000–5000mU/L),in microprolactinomas, serumprolactinlevelsareusually if nootherexplanationsforamenorrheaarefound.In hormoneexcessordeficiency,suggesting pituitary or results to othercauses,clinicalsignsorlaboratory neurologic signs,thirstorurinationnotattributable that isnotself-induced,changeinvision,lateralizing occupying lesion:severeorpersistentheadache,vomiting hypogonadotropic hypogonadismviamasseffect. histiocytosis, anddermoidorepidermoidcystscancause ( space-occupying lesions,suchascraniopharyngiomas GnRH stimulationhastobe reviewed( sensitivityto hyperprolactinemia ordecreasing pituitary serum prolactinlevelsandthe HPOaxis. pathology willusuallyresult inthenormalizationof ( ( deficienciesduetomutations inhemojuvelin pituitary hypogonadotropic hypogonadismwithnoadditional (type 2)canpresentwithdelayedpubertyorpermanent to dopamine suppression ( latter maybeduetoreducedlactotrophresponsiveness prolactin, and increased prolactin secretion( due toimpairedrenaldegradationandclearance of insufficiency maycausemoderatehyperprolactinemia tumor( hyperplasia thatmaymimicapituitary hypothyroidismcancausepituitary treated primary inhibits GnRHpulsation( prolactin releasecausinghyperprolactinemia,which hypothalamus. Subsequently, TRHstimulatesTSHand thyrotropin-releasing hormone(TRH)secretioninthe axisleadingtoincreased hypothalamus–pituitary–thyroid hyperprolactinemia vialackofnegativefeedbackinthe hypothyroidismmaycausemoderate Primary hypogonadotropic hypogonadism Other acquiredcausesofhyperprolactinemiaor in ( initial treatment followed bymedical therapy (reviewed hyperprolactinemia, trans-sphenoidal resectionisthe Primary amenorrhea 50 HAMP HJV ), , Rathke’s cleft cyst, Langerhans cell 49 Use of any medication or drug causing Use ofanymedication ordrugcausing Dopamine agonistscabergolineandbromocriptine Brain MRIisindicatedinasuspicionofspace- ) gene(type2A)orhepcidinantimicrobialpeptide )). ) gene (type 2B) ( Downloaded fromBioscientifica.com at09/25/202104:20:59PM 52 25 25 ). Treatment of the underlying ). Long-termorinadequately ). Juvenile hemochromatosis https://eje.bioscientifica.com 184 :6 Table 1 48 ). Opiates ). Opiates 48 51 ). Renal R233 ). The )). via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com in ( the mostcommoncausesfor CPHDinhumans(reviewed for thedevelopmentofgonadotropin-secreting cells,are Autosomal recessivemutations in midline defects or with other clinical findings ( deficiency and a wide spectrum of craniofacial or other cause syndromichypopituitarismwithgonadotropin GLI2, POU1F1,LHX4,PITX1,OTX2 as adolescence ( evolves overtime,withthelastdeficiencypresenting in gland( pituitary stalk interruptionsyndromewithectopicposterior deficiencies, componentofothersyndromes,orpituitary ( a varietyofsyndromicandnon-syndromicpresentations . Itsgeneticbasiscomprisesover30geneswith by impaired production of at least twoanterior pituitary either anacquiredorcongenitaldisordercharacterized hormonedeficiency(CPHD)canbe Combined pituitary Combined pituitaryhormonedeficiency(CPHD) exist ( amenorrhea case reportsinadolescentswithprimary hypophysitis occurstypicallyduringpregnancybutalso rare. gland is very infiltrateLymphocytic in the pituitary and hypopituitarism.Hypophysitis,aninflammatory hemorrhage or trauma maycause GnRH deficiency axis damageduetoinflammation,infection,ischemia, from theposteriorpituitary. Hypothalamic–pituitary orreleased hormones producedbytheanteriorpituitary Hypopituitarism referstodeficiencyofoneormore Hypopituitarism antidopaminergic modeofaction(reviewedin( may causehyperprolactinemiaandamenorrheathrough metoclopramide anddomperidone)antihypertensives Certain gastrointestinalmotilityagents(suchas such asfluoxetinemaycausehyperprolactinemia. risperidone ( than atypicalantipsychotics,withtheexceptionof more robusteffectonelevatingprolactinconcentrations secretion (reviewedin( effectofdopamineonprolactin diminish theinhibitory dopaminereceptors,which antagonistic effectonpituitary and clinicalhypogonadism( suppress LHsecretion,resultinginlowsexsteroidproduction 56 Review HESX1, LHX3 ). It may manifest as isolated pituitary hormone ). It may manifest as isolated pituitary 1 Mutations in several transcription factors, such )). 55 ). 54 55 ). Selective serotonin reuptake inhibitors ). Selectiveserotoninreuptakeinhibitors ). 10 , SOX2, PITX2,GATA2, ERG1, NR5A1, ). Insomeinstances,hypopituitarism 20 )). Typical antipsychoticshavea 53 ). Neuroleptics have an ). Neurolepticshavean S Seppäandothers PROP1, and beingimportant SOX3 25 1 , )). 55 , 57 can ). complete pituitary axis (prolactin, FT4, TSH, morning complete pituitary insufficiencyissuspected,explorationofthe If pituitary Evaluation andtreatmentofhypopituitarism (reviewed in( tumors pharmacological orradiotherapyofpituitary syndrome canoccuraftertrans-sphenoidalneurosurgery, empty sella complications, or geneticdisorders.Secondary dysfunction, perinatal with hypothalamic–pituitary sella syndromeisrareinchildrenandoftenassociated empty dysfunction.Primary cavity wallscausingpituitary parenchymacompressionagainstthesellar and pituitary by herniationofthesubarachnoidspacewithinsella congenital defectinthesellardiaphragm.Itischaracterized regionduetoa a raredisorderoftheanteriorpituitary emptysellasyndromeis hormonal secretion.Primary in brainMRIwithoutanysymptomsordeficiencies ( 4 weeksapartandlowE2 levels before40yearsofage gonadotropin levelsontwo occasionsseparatedatleast as menstrual absence or irregularity with elevated Premature ovarian insufficiency (POI) is defined Premature ovarianinsufficiency(POI) until adolescence. congenital ovarianfailure/agenesismaygounrecognized production isrelativelyquiescentduringchildhood, gonadal function prenatally, and sinceovarianhormone of phenotypic female genitalia does not require active and elevated gonadotropin levels. Since the development unit of negativefeedbackonthehypothalamic–pituitary Failure of the ovarian hormone production results in lack hypergonadotropic hypogonadism Etiologies causing described laterinthisreview. patient ( of bone and cardiovascular health and wellbeing of the oftheunderlyingcause,andmanagement surveillance hormonedeficiencies, the developmentofnewpituitary desmopressin andhydrocortisone),regularscreeningfor hormonal deficiencies (thyroxine, sex steroids, GH, ( challenge testsandbrainMRIshouldbeperformed cortisol, ACTH,-likegrowthfactorI),dynamic Primary amenorrhea 59 55 ). Thediagnosticincreasein FSHlevelvariesaccording ). Managementincludesreplacementtherapyof Empty sella is most often found by a coincidence 55 ). Treatment ofgonadotropindeficiencyis 58 )). Downloaded fromBioscientifica.com at09/25/202104:20:59PM 184 :6 R234 via freeaccess European Journal of Endocrinology may bepresent(suchasring Xchromosome). ( 10–12%) oracelllinewith threeXchromosomes(3%) (45,X/46,XX; 15–25%),a46,XY cellline(45,X/46,XY; is acelllinewithXmonosomy anda46,XXcellline 45,X)( completely (karyotype (40–50% of cases), the other X chromosome is missing ( Turner syndrome is approximately50/100 000 females cause ofPOIinadolescents( Turner syndromeisthemost commonnon-iatrogenic Turner syndrome POI diagnosis. support should be offered to all adolescents at the time of issues maybeemotionallydevastating,andpsychological team iswarranted.DiagnosisofPOIandassociatedfertility neurological sequelae, and follow-up of a multidisciplinary associated withcardiovascular, psychological,sexualand amenorrhea( vssecondary primary BMD hasbeenreportedinwomenwithPOIpresentingas members) ( discussed first (associated intellectual disability in family significance andconsequencesofapositiveresultare premutation testingshouldnotbeobtainedunlessthe autosomal genetictestingisnotrecommended.Fragile-X peroxidase antibodiesshouldbeconsidered.Routine antibodies (oradrenocorticalantibodies)andthyroid analysis isnormal,screeningof21-hydroxylase syndrome and46,XYgonadaldysgenesis.Ifchromosomal analysis isakeydiagnostictesttoruleoutTurner cases ( however, itsetiologystillremainsunknowninmany over 75geneshavebeenfoundinassociationwithPOI; 65 of POI has been reported in 12–14% of POI women ( syndromic POI(reviewedin( and singlegenemutationsleadingtosyndromicornon- include ovarianautoimmunity, ,pelvicsurgery found in30.7%ofthem( in14%andchromosomalabnormalitywas was observed amenorrhea Chinese POIcohortof955women,primary (chemotherapy or radiation therapy) ( or iatrogeniccausessuchaspreviouscytotoxictreatment and mostoftenassociated with chromosomal aberrations amenorrheaisrare adolescence orpresentingasprimary to source from 68 67 Review ). The genetic background is diverse and mutations in ). Structuralaberrations of thesecondXchromosome ). InthemostcommonformofTurner syndrome POI hasanegativeimpactonbonehealthandlower In asuspicionofnon-iatrogenicPOI,chromosomal 66 ). 59 ). > 25 IU/L( 63 ). Otherlesscommonetiologies 58 64 ) to 68 61 )) ( ). Inmosaicforms,there S Seppäandothers , > 62 65 Fig. 3 40 IU/L( ). Theincidenceof ). Inaddition,POIis 61 ). Family history ). Familyhistory , 62 ). In a large 60 ). POIin 63 , of spontaneousthelarche and menarche werelowest, therates of 13.2years.Ingirlswith45,Xkaryotype, and spontaneous menarche in20.8% at the average age was reportedin32%attheaverageageof12.3years, girls withTurner syndrome ( recent systematicreviewincludingdatafromover2500 results inPOIprepubertallyorduringadolescence.Ina starts prenatallyanddepletionoftheovarianfolliclepool (presented inrecentclinicalpracticeguidelines( and morbiditiesshouldbecommencedafterdiagnosis during 1961–2014)( at diagnosishasbeenlate(15.1yearsinaDanishregistry diagnosis of Turner syndrome; however, the median age Phenotypic featuresmayleadtoprenatalsuspicionand tumors ( because oftheincreased risk ofmalignantgermcell Y-chromosomal material,gonadectomy is recommended of diagnosis( concerning thefertilityissues isstartedatthetime Turner syndrome.Itisrecommended thatcounselling complications, both maternal and fetal, is increased in are required to treat infertility. The risk of pregnancy the majorityofcases,assistedreproductivetechnologies with Turner syndrome have been reported; however, in years ( girls, theinductionmaybedelayed,however, notpast14 induction from the ageof 11–12 years ( to beasignofovarianfailureandanindicationforpubertal over 10 IU/L at 10 years of ageinTurner girls is considered long periodofothergrowthpromotingtherapies.FSHlevel replacement shouldbestartedwithlowdosestoallowfora are possible( alone; however, associatedsymptomsofvirilization may resultinabettergainofheightthangrowthhormone diagnosis, treatmentwithoxandrolone(ananabolicsteroid) i epiphyseal closureonanX-rayofthelefthandandwrist, the remaining growth potential (evaluated as the level of girls withTurner syndromebutincaseoflatediagnosis, linear growth.GHtherapyisastandardtreatmentinshort spontaneous menarche from13 to66%. spontaneous thelarche ranged from31to88%andthatof 13 and9.1%respectively. Inmosaicforms,therateof and milderphenotypesareseeninmosaicforms( congenital heartdisease(50%)andkidneyanomalies, (95–100%), characteristicfacialandskeletalsigns, Primary amenorrhea . e . bone age) may be limited. In some cases with late boneage)maybelimited.Insomecaseswithlate Accelerated lossofgermcellsinTurner syndrome In rarecases,spontaneouspregnanciesinwomen HRT inTurner syndromeshouldbeoptimizedfor Typical phenotypicfeaturesincludeshortstature 71 68 ) andalsolongertimeforinductioncouldbeused. ). 68 68 ). IngirlswithTurner syndromewith ). If growth potential exists, estrogen ). Ifgrowthpotentialexists,estrogen 67 ). Screeningofassociatedfeatures Downloaded fromBioscientifica.com at09/25/202104:20:59PM 69 https://eje.bioscientifica.com ), spontaneous thelarche 184 70 :6 ). In very short short ). In very 68 R235 )). 68 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com recommends gonadectomyatthetimeofdiagnosis( risk ofgermcelltumors,therecentconsensusstatement amenorrhea.Duetoasignificant pubertal delayorprimary 000 ( adrenal development( appearance involvingforexample,defectsinrenaland complete gonadaldysgenesis,sometimeswithsyndromic 16 geneshavebeendescribedinassociationwith46,XY developsintoovary, ovotestisorastreak.Atleast Instead, genitaliadevelopintoatypicalfemaleandthe testis developmentandpreventionofmasculinization. differentiation (e.g. gonadal development(e.g. hormone production,mutationsingenesaffectingearly external and internal genitalia requires active testicular developmentofphenotypicmale Since theembryonic amenorrhea( delayed pubertyorprimary (46,XY)inanadolescentgirlwitheither karyotype Sometimes chromosomalanalysismayrevealamale primary amenorrhea presenting asdelayedpubertyor 46,XY differencesofsexualdevelopment(DSD) or pubichair( of testicularandrogenstoestrogens) butscantyaxillary with someorfullbreast development (aromatization amenorrhea presentation inanadolescent isprimary hernia mayleadtoprepubertaldiagnosis;however, typical normal orhighLHlevels.Presentationwithinguinal 000 women( defect in46,XYfemaleswithprevalenceof4.1/100 mutations inthe it developsintoavaginalpouch. and normallyfuseswiththeupperpartbutinthesecases origin (urogenital sinus) vagina isofdifferentembryonic anduppervagina. Distal fallopian tubes,uterus,, Müllerian structuresregressleadingtoabsenceofthe hormone secretion remains intact in these conditions, Becausetesticularanti-Müllerian with 46,XYkaryotype. hernias), andlackofWolffian structuresingeneticmales undescended testes(sometimesmisdiagnosedasinguinal phenotypic femaleexternalgenitaliawithabdominalor ( enzymes (e.g. resistance ( team beforegonadectomyisessential. DSD Discussion betweenthefamilyandmultidisciplinary Review Androgen insensitivitysyndrome(AIS)dueto Defects in androgen production due to gonadotropin The prevalenceof46,XYgonadaldysgenesisis1.5/100 73 ). Thediagnosisistypicallymadeinpubertydueto LHCGR 73 ). Testosterone highwith levelsarevery 73 CYP17A1 mutation), mutations in steroidogenic AR ). Mildclitoralenlargement maybe AR SRY gene isthemostcommongenetic 72 ) mayresultindevelopmentof , ). , SOX9 SRD5A2 WT1 ) may lead tofailure in S Seppäandothers , , NR5A1 HSD17B3 Figs 2 ) orgonadal ) orthe and 74 3 ). ). Perrault syndrome,ovariandysgenesisisassociatedwith except forstreakovaries.Ingeneticallyheterogeneous development withnormalfemalereproductiveorgans of ovarian dysgenesis is absent or incomplete pubertal or ovarianestrogenproduction.Theclinicalpresentation involved ingonadaldevelopment(ovariandysgenesis) insufficiency maybecausedbymutationsingenes If no sex chromosomal aberration is detected, ovarian primary amenorrhea 46,XX DSDpresentingaspubertaldelayor israrelyrequired( vaginal pouch enables , surgical spontaneous ( gonadectomy maybepostponedafterpubertyallowing a germcelltumorislowerthaninpartialAIS(PAIS) and the complete form of AIS (CAIS), the risk of developing present dependingonthedegreeofARinsensitivity. In there isanevidenceofclinical hyperandrogenism,serum baldness), clitoralenlargement andvoicedeepening.If severe acne,hirsutism,androgenic alopecia(malepattern in associationwithprevious prematureadrenarche, amenorrhea menstrual disturbancesincludingprimary Androgen excessmaypresentinadolescentgirls as Primary amenorrheaandandrogenexcess normogonadotropic hypogonadism Etiologies causingprimaryamenorrheawith to theblockinFSHaction( stagedue and folliculardevelopmentishaltedtoprimary contrast, ovaries in girls with conditions due tohighgonadotropin stimulation. In ( is observed which worsensatpubertyandnobreastdevelopment girl isusuallydetectedalreadyatbirthduetovirilization, cortisol. Aromatasedeficiency( prevented byhigh corticosterone levels thatsubstitute hypertension andhypokalemia( girl withlackofpubertaldevelopment,low-renin gonads andadrenalsmaypresentasanadolescent CYP17A1 CYP19A1 mutations in steroidogenic enzymes (e.g. by gonadotropinresistance(e.g. bilateral sensorineuralhearingdefect( Primary amenorrhea Ovarian estrogenproductionmaybeblocked ) blockstheproductionofC19steroidsinboth ). 17-hydroxylasedeficiency(mutationin 77 ). Ovariancystsmaybepresentinboth Downloaded fromBioscientifica.com at09/25/202104:20:59PM 64 ). FSHR 75 CYP19A1 ). 76 mutations are small FSHR 74 184 ). Adrenalcrisisis 64 ). Dilation of the :6 ). mutations)or mutation)ina CYP17A1 R236 via freeaccess , European Journal of Endocrinology gene is recommended, and compound heterozygous forms diagnostic forthedisease. Genetic analysisof test: stimulated17-OHPlevel and shouldbecontrolled with anACTHstimulation morning levelof17-OHP 1:100 to1:2000women( between ethnicitiesandhasbeenestimatedtobefrom or ( amenorrhea/menstrual irregularity hirsutism, primary present asprematurepubarche/adrenarche, severeacne, Newborn screeningrarelydetectsNCAH.Itmay until laterinchildhoodorsometimesevenadulthood. CAH), thesymptomsofandrogenexcessarenotpresent due to21-hydroxylasedefect(themostcommonform of In non-classic congenital adrenal hyperplasia (NCAH) Non-classic congenitaladrenalhyperplasia(NCAH) metformin ( combinedoralcontraceptivepillsand intervention, is justified.ThetreatmentofPCOSincludeslife-style amenorrhea hypertension inPCOSpatientswithprimary for type2diabetes,insulinresistance,dyslipidemia,and ( amenorrheaor in comparisontoPCOSwithsecondary levels, andhigherprevalenceofacanthosisnigricans such ashighertestosterone,insulinandtriglyceride been associated with moreseveremetabolicdisturbances amenorrhea has diagnosis. In PCOSadolescents, primary is a common feature but not required for or overweight follicular appearanceiscommonforage( required forPCOSdiagnosisinadolescentssincemulti- PCOS ( amenorrhea andexclusionofotherconditionsthatmimic immunoassays) withmenstrualirregularityorprimary or extraction/chromatography mass spectrometry bioavailable testosteroneusingliquidchromatography– (calculated freetestosterone,androgenindexor adolescence areclinicalorbiochemicalhyperandrogenism ( oligomenorrhea isthemosttypicalmenstrualdisturbance amenorrheaalthough more commonlysecondary or in adolescentgirls.PCOSmaypresentasprimary PCOS isthemostcommonhyperandrogenicdisorder Polycystic ovarysyndrome(PCOS) levels shouldbeobtained( (free) testosterone,DHEA-S,androstenedioneand17-OHP 78 Review ). ThesuggesteddiagnosticcriteriaforPCOSin 79 , 80 80 ). Polycystic ovarian morphology is not ). 78 82 , ). TheprevalenceofNCAHvaries 81 ). Therefore, routine evaluation > 6 nmol/LissuggestiveofNCAH 20 83 ). ). Non-stimulated,early > S Seppäandothers 30nmol/L at60minis 79 ). Obesity CYP21A2

cause ‘exogenousCushing’s syndrome’( syndrome’), therapeuticallyusedglucocorticoids may hypercortisolism (representing ‘endogenous Cushing’s carcinomas. In addition to all above mentioned forms of cortisol overproductionbyadrenaladenomasor by neuroendocrineneoplasmsandACTH-independent may also be due to ectopic ACTH or CRH production hyperandrogenism duetoACTHexcess.Hypercortisolism ovarian origin.Cushing’s diseasemayresultinadrenal are seeninandrogensecretingtumorsofadrenal( Highly elevatedDHEA-Sand/orandrostenedionelevels in adolescence Rare causesofandrogenexcessorvirilization treatment tosuppressandrogenlevels( in anNCAHpatientisindicationforhydrocortisone or are typical.OtherformsofNCAH(mutationsin the vagina(). Cyclicoracutepelvic blueish ordarkcolorcaused bytheretainedbloodin Imperforate hymenmaypresent asabulgingmassin Imperforate hymen amenorrhea( women withprimary genital examinationisabnormalinapproximately15% of organs withultrasonographyandMRI( examination withimagingoftheinternalreproductive fusion. Inthisscenario,theapproachisagynecological urogenital sinus (hymen, distal vagina) or a defect in their upper vagina)or of theMüllerianducts(uterus,cervix, may becausedbycongenitalanomaliesofthederivatives development andnormogonadotropichypogonadism normalpubertal amenorrheawithotherwise Primary Anatomical causesofprimaryamenorrhea birth andvirilizationduringpuberty. in 46,XXDSDisassociatedwithambiguousgenitaliaat positive testisneededtoconfirmthediagnosis( suppression canbeusedasscreeningtests.Additional cortisol,ora1-mgovernightdexamethasone night salivary freecortisol,late- syndrome issuspected,a24-hurinary puberty. Aromatasedeficiencydueto genitalia atbirthbutprogressivevirilizationduring cause 46,XYDSDpresentingwithfemale/ambiguous and 17 Primary amenorrhea HSD3B2 Mutations ingenesencoding5 β -hydroxysteroid dehydrogenase3( ) areextremelyrare( Downloaded fromBioscientifica.com at09/25/202104:20:59PM https://eje.bioscientifica.com 83 α ). Primary amenorrhea ). Primary 17 -reductase-2 ( 184 CYP19A1 ). 82 :6 85 ). 87 ). IfCushing’s ) ( mutations HSD17B3 Fig. 2 86 CYP11B1 SRD5A2 R237 ). 84 ). A ) or via freeaccess ) )

European Journal of Endocrinology https://eje.bioscientifica.com exist ( surgical treatment.Different treatmentmodalities and pelvic adhesions which maycomplicate flow resultsinhematometra, retrogrademenstrualflow, with vaginal agenesis. Obstruction of the menstrual agenesismaybeisolatedbutis oftenassociated Cervical Cervical agenesis endometriosis ( and retrogrademenstruationareassociatedwith to prevent further uterine bleeding ( oral contraceptivepillsorGnRHanalogscanbeused Prior to operative treatment, continuous combined ( operative complicationsandneedforre-surgery septae are associated with the higher rate of post- be performedinspecializedcenters.Highandthick risk ofcomplications.Asurgicalmanagementshould laparoscopy orvaginalapproach)tominimizethe aids inchoiceofthebestsurgicalapproach(laparotomy, or thin( thickness (determinedbyMRIasthick( 72%), mid (3–6 cm, 22%) and high ( septa hasbeendefinedaslow( and thicknessofthesepta( and presurgical evaluation should include the location anomalies inBritain( patient seriesfromaspecializedcenterforMüllerian of imperforate transverse septae was 14.3 years in a and abdominalorpelvicpain.Themeanageofdiagnosis vaginal anduterineenlargement(hematometrocolpos) imperforate, theobstructedmenstrualbloodmaycause sinus resultintransversevaginalseptum.Iftheseptumis Failure offusionthevaginalplateandurogenital Transverse vaginalseptum Urologic oranorectalanomaliesmaybeassociated( shows pink mucosa without hymenal tissue or a bulge. In distalvaginalatresia,evaluationofexternalgenitalia Distal vaginalatresia expected ( is byasurgicalincision,andlong-termsequelaearenot . If these can be excluded, the management from labialadhesions,distalvaginalatresiaandtransverse examination, imperforatehymenshouldbedifferentiated retention may present. On and urinary Review 92 ). < 88 1 cm))( ). 89 ). 90 ). Acarefulpresurgicalevaluation 90 ). Themanagementisoperative 89 , < 91 3 cmfromtheintroitus, S Seppäandothers ). Thelocationofthe > 6 cm, 6%), and the 89 ). Obstruction > 1cm,46%) 89 90 ). ). ).

endometrial hyperplasiaand irregularbleeding. 1–3 monthsprotectsfromestrogen-induced for every the initiation of cyclic progestin. Ten days of progestin evaluated by transabdominalultrasonographyto optimize replacement. Thethicknessofendometriummaybe bleeding occursorafter2–2.5yearsofunopposedestrogen explained carefully. Progestinisaddedwhen breakthrough compliance andbenefitsofthetreatmentshould be Individualization ofthetreatmentmayresultinbetter andinfluences thechoiceoftreatment. tocountry country The availability of hormonal preparations varies from 6months could beused( or fixedincrementsforevery to givebirth( transfer,and womenwithMRKHhavebeen able gestational surrogacy. Asaresultofuterinetransplantation vaginoplasty. Geneticmotherhoodispossiblebyusing by non-invasivevaginaldilatation(first-linetherapy)or genetic backgroundisnotclear. Vaginal agenesisistreated hearing andcardiaccomplications may beassociated.The DSD withsimilarpresentation( aids in differentiating Müllerian agenesis from 46,XY complaint leadingtodiagnosis.Chromosomalanalysis amenorrheaisatypical and blind-endedprimary external genitaliaaretypicalfemalebutthevaginaisshort sexualcharacteristicsdevelopnormally,Secondary and Estimatedprevalenceis1:5000women. 46,XX karyotype. uterus anduppertwo-thirdsofvaginainwomenwith Müllerian ductdevelopmentresultinginagenesisofthe Küster–Hauser (MRKH)syndromeisafailureofthe Müllerian agenesis,alsoknownasMayer–Rokitansky– Müllerian agenesis is preferred.Thedosemaybetitratedforbodyweight( natural 17 girls, in general( for girlswithTurner syndrome( administration have been describedin recent review articles Detailed instructionsforeithertransdermalororalestrogen and graduallyincreasedover2–3yearstofulladultdose. achievement ofnormalpeakbonemass. spurt thatresultsinadultheightclosetoexpected,and -shaped uterusenablingpossiblelaterpregnancies,growth to induceproperbreastdevelopment,adult-sizedand magnitude as in peers. More specifically, theaims are and psychosocialdevelopmentatasimilartempo hypergonadotropic hypogonadism and aim at physical in girls is similar in both hypogonadotropic and induction andmaintenanceofpubertaldevelopment Induction andmaintenanceofpubertaldevelopmentThe Primary amenorrhea Estrogen replacement is initiated with small doses Estrogen replacementisinitiatedwithsmalldoses β -estradiol instead of synthetic ethinyl estradiol -estradiol insteadofsyntheticethinylestradiol 93 ). 94 , 95 ). In general, transdermal route and ). In general, transdermalroute and Downloaded fromBioscientifica.com at09/25/202104:20:59PM 70 Fig. 2 , 184 71 ). Renal,skeletal, ) or hypogonadal ) orhypogonadal :6 R238 71 70 via freeaccess ). ). ) European Journal of Endocrinology the public,commercialornot-for-profit sector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofresearchreported. no is there that declare authors The Declaration ofinterest where nocurabletreatmentexists. diagnosis fertilitymaybeattainedeveninthosesituations fertility isalwaysthreatened.However, withtimely reproductive capacityisquitegood,whereasinPOI, pathologies intheabsenceofamalefactorinfertility, in patientswith permanent hypogonadism. In central progesterone, andlatermorecomplexmanagement medication torecompensethelackofestrogenand sexual maturationorinfertility. Treatment involves psychological burdenassociatedwithdelayedorarrested (if needed), and psychological support alleviate the should not be neglected. Early diagnosis, timely HRT genetic testingisnotrecommended. is notyetasadvanced,andtherefore,routineautosomal the diagnosisofCHHandNCAH,inPOI,genetictesting should beusedcautiously;althoughitisrecommendedin amenorrhea.However,underlying primary genetic testing organs. Gene discoveries are expanding in several fields transabdominal sonographyoftheinternalreproductive approach isexternalgynecologicalexaminationwith despite normalpubertaldevelopment,thefirst-line amenorrhea Especially in youngerfemaleswithprimary between the pediatric endocrinologist and gynecologist. amenorrhea inteenagersoftenneedscollaboration dysfunction andinfertility. Diagnosticsofprimary related problems,feelingsofdefeminization,sexual innate problems of the underlying etiology, hypoestrogen- dependingonitscauseandinclude health risksvary amenorrhea. Its long-term tract may underlie primary Multiple etiologiesaffecting the HPOaxisandoutflow Conclusions has beenusedfor1to2years. Finally, BMDshouldbemeasuredafterafulldoseofHRT to confirmthediagnosisandneedforpermanentHRT. spontaneous HPO axis function should be performed of withdrawal ofhormonereplacementandobservance may notbeindistinguishable from CDGP, temporal Review The psychosocial impact of primary amenorrhea The psychosocial impact of primary Since permanenthypogonadotropichypogonadism S Seppäandothers References

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Accepted 9March2021 Revised versionreceived18February2021 Received 31December2020

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